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Brain Advance Access originally published online on August 10, 2006
Brain 2006 129(10):2734-2745; doi:10.1093/brain/awl207
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia

H. Liu1, O. Honmou1,3,4, K. Harada1, K. Nakamura2, K. Houkin1, H. Hamada2 and J. D. Kocsis3,4

1 Departments of Neurosurgery, Sapporo Medical University School of Medicine Sapporo, Japan 2 Molecular Medicine, Sapporo Medical University School of Medicine Sapporo, Japan 3 Department of Neurology, Yale University School of Medicine New Haven 4 Neuroscience Research Center, VA Medical Center West Haven, CT, USA

Correspondence to: Osamu Honmou, MD, Department of Neurosurgery, Sapporo Medical University School of Medicine, South-1st, West-16th, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan E-mail: honmou{at}sapmed.ac.jp

Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PlGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PlGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PlGF gene (PlGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PlGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PlGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PlGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PlGF in both hMSC groups, but a greater increase in the PlGF-hMSC group. These data support the hypothesis that PlGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PlGF to the brain can be achieved by intravenous delivery of hMSCs.

Key Words: angiogenesis; bone marrow transplantation; neural transplantation; regeneration; stroke

Abbreviations: BDNF, brain-derived neurotrophic factor; DWIs, diffusion-weighted images; ELISA, enzyme-linked immunosorbent assay; hMSCs, human MSCs; MCAO, middle cerebral artery occlusion; MOI, multiplicity of infection; MSCs, mesenchymal stem cells; PBS, phosphate-buffered saline; PlGF, placental growth factor; TTC, 2,3,5-triphenyltetrazolium chloride; TUNEL, terminal deoxynucleotidyltransferase dUTP nick-end labelling; VEGF, vascular endothelial growth factor

Received January 24, 2006. Revised June 1, 2006. Accepted June 1, 2006.


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